Human immunodeficiency virus-1 (HIV-1) is the causative agent of acquired immune deficiency syndrome (AIDS) and related disorders (Gallo, R. C. et al. (1983) “Isolation of human T-cell leukemia virus in acquired immune deficiency syndrome (AIDS),” Science 220(4599):865-7; Barre-Sinoussi, F. et al. “ISOLATION OF A T-LYMPHOTROPIC RETROVIRUS FROM A PATIENT AT RISK FOR ACQUIRED IMMUNE DEFICIENCY SYNDROME (AIDS),” (1983) Science 220:868-870; Gallo, R. et al. (1984) “FREQUENT DETECTION AND ISOLATION OF CYTOPATHIC RETROVIRUSES (HTLV-III) FROM PATIENTS WITH AIDS AND AT RISK FOR AIDS,” Science 224:500-503; Teich, N. et al. (1984) “RNA TUMOR VIRUSES,” Weiss, R. et al. (eds.) Cold Spring Harbor Press (NY) pp. 949-956).
T lymphocytes and macrophages expressing CD4 and the seven transmembrane chemokine co-receptors CXCR4 and CCR5 are susceptible to HIV-1 infection (Berger, E. A. et al. (1999) “CHEMOKINE RECEPTORS AS HIV-1 CORECEPTORS; ROLES IN VIRAL ENTRY, TROPISM, AND DISEASE,” Annu. Rev. Immunol. 17:657-700). In contrast to CD4+ lymphocytes, HIV-1 infected macrophages can resist cell death despite viral infection. Viruses within and shed from infected macrophages may serve as a reservoir for the infection of additional cells (Wahl, S. M. et al. (1996) In: MACROPHAGE FUNCTION IN HIV INFECTION, pages 303-336; Orenstein, J. W. (2001) “THE MACROPHAGE IN HIV INFECTION,” Immunobiology 204(5):598-602; Balestra, E. et al. (2001) “MaCROPHAGES: A CRUCIAL RESERVOIR FOR HUMAN IMMUNODEFICIENCY VIRUS IN THE BODY,” J. Biol. Regul. Homeost. Agents 15:272-276; Igarashi, T. et al. (2001) “MACROPHAGE ARE THE PRINCIPAL RESERVOIR AND SUSTAIN HIGH VIRUS LOADS IN RHESUS MACAQUES AFTER THE DEPLETION OF CD4+ T CELLS BY A HIGHLY PATHOGENIC SIMIAN IMMUNODEFICIENCY VIRUS/HIV TYPE 1 CHIMERA (SHIV): IMPLICATIONS FOR HIV-1 INFECTIONS OF HUMANS,” Proc. Natl. Acad. Sci. U.S.A. 98:658-663; Garbuglia, A. R. et al., (2001) “DYNAMICS OF VIRAL LOAD IN PLASMA AND HIV DNA IN LYMPHOCYTES DURING HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART): HIGH VIRAL BURDEN IN MACROPHAGES AFTER 1 YEAR OF TREATMENT,” J Chemother 13:188-194).
The persistence of HIV during highly active antiviral therapy, and poor susceptibility of macrophages to antiviral therapy (Igarashi, T. et al. (2001) “MACROPHAGE ARE THE PRINCIPAL RESERVOIR AND SUSTAIN HIGH VIRUS LOADS IN RHESUS MACAQUES AFTER THE DEPLETION OF CD4+ T CELLS BY A HIGHLY PATHOGENIC SIMIAN IMMUNODEFICIENCY VIRUS/HIV TYPE 1 CHIMERA (SHIV): IMPLICATIONS FOR HIV-1 INFECTIONS OF HUMANS,” Proc Natl Acad Sci USA 98:658-63; Garbuglia, A. R. et al. (2001) “DYNAMICS OF VIRAL LOAD IN PLASMA AND HIV DNA IN LYMPHOCYTES DURING HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART): HIGH VIRAL BURDEN IN MACROPHAGES AFTER 1 YEAR OF TREATMENT,” J Chemother 13, 188-94) has intensified the interest in characterizing the mechanisms underlying infection and replication in this cell population.
Attempts to treat HIV infection have focused on the development of drugs that disrupt the viral infection and replication cycle (see, Mitsuya, H. et al. (1991) “TARGETED THERAPY OF HUMAN IMMUNODEFICIENCY VIRUS-RELATED DISEASE,” FASEB J. 5:2369-2381). Such intervention could potentially inhibit the binding of HIV to cell membranes, the reverse transcription of the HIV RNA genome into DNA, the exit of the virus from the host cell and infection of new cellular targets, or inhibition of viral enzymes (see, U.S. Pat. No. 6,475,491). Thus, for example, soluble CD4 has been developed in an effort to competitively block the binding of HIV to lymphocytes (Smith, D. H. et al. (1987) “BLOCKING OF HIV-1 INFECTIVITY BY A SOLUBLE, SECRETED FORM OF THE CD4 ANTIGEN,” Science 238:1704-1707; Schooley, R. et al. (1990) “RECOMBINANT SOLUBLE CD4 THERAPY IN PATIENTS WITH THE ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS) AND AIDS-RELATED COMPLEX. A PHASE I-II ESCALATING DOSAGE TRIAL,” Ann. Int. Med. 112:247-253; Kahn, J. O. et al. (1990) “THE SAFETY AND PHARMACOKINETICS OF RECOMBINANT SOLUBLE CD4 (RCD4) IN SUBJECTS WITH THE ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS) AND AIDS-RELATED COMPLEX. A PHASE 1 STUDY,” Ann. Int. Med. 112:254-261; Yarchoan, R. et al. (1989) Proc. Vth Int. Conf. on AIDS, p 564, MCP 137). Similarly, the ability of antisense HIV-1 oligonucleotides to inhibit viral replication has been investigated (Maeda N et al. (1998) “INHIBITION OF HUMAN T-CELL LEUKEMIA VIRUS TYPE 1 REPLICATION BY ANTISENSE ENV OLIGODEOXYNUCLEOTIDE,” Biochem Biophys Res Commun 243(1): 109-112).
Unfortunately, although considerable effort has been expended to design effective therapeutics, no curative anti-retroviral drugs against AIDS currently exist. All available therapies are marred by substantial adverse side effects, and by the capacity of HIV to rapidly mutate into forms that are refractive to treatment (Miller, V. et al. (2001) “MUTATIONAL PATTERNS IN THE HIV GENOME AND CROSS-RESISTANCE FOLLOWING NUCLEOSIDE AND NUCLEOTIDE ANALOGUE DRUG EXPOSURE,” Antivir Ther. 6 Suppl 3:25-44; Lerma, J. G. et al. (2001) “RESISTANCE OF HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 TO REVERSE TRANSCRIPTASE AND PROTEASE INHIBITORS: GENOTYPIC AND PHENOTYPIC TESTING,” J Clin Virol. 21(3):197-212; O'Brien, W. A. (2000) “RESISTANCE AGAINST REVERSE TRANSCRIPTASE INHIBITORS,” Clin Infect Dis. 30 Suppl 2:S185-92; Wain-Hobson, S. (1996) “RUNNING THE GAMUT OF RETROVIRAL VARIATION,” Trends Microbiol. 4(4):135-41; Lange J. (1995) “COMBINATION ANTIRETROVIRAL THERAPY. BACK TO THE FUTURE,” Drugs. 49 Suppl 1:32-40). Thus, a continuing need exists for safe and effective anti-HIV therapeutics. The present invention is directed to this and other needs.